Cutaneous malignant melanoma incidence continues to rise, and prevention is still the best way to fight against the disease, yet efficient prevention strategies are hindered by the lack of knowledge of the mechanisms involved in melanomagenesis. The carcinogenic pathways that lead to the malignant transformation of epidermal melanocytes (hMCs) to melanoma seem to differ from those that lead to the transformation of keratinocytes in basal or squamous cell carcinoma tumors. While keratinocyte-derived tumors commonly present typical "UV signature" mutations, particularly in the TP53 gene, such mutations are rare in melanoma tumors. Although there is compelling evidence for the role of ultraviolet radiation (UVR), for at least a subset of melanoma tumors that arise in sun exposed areas of the body, DNA photoproducts that are directly induced by UVR, do not seem to be the main cause for the genetic alterations in melanoma-associated genes. Mutations in p16 and BRAF genes, which are suggested to be induced by oxidative stress, underscore the central role of UVR-induced oxidative stress in hMC malignant transformation to melanoma. Studies addressing the mechanisms that counteract UVR-induced oxidative stress in hMCs, have important clinical and public health implications since they should provide novel means for melanoma prevention strategies. The objective of this proposal is to test the central hypothesis that a-melanocyte stimulating hormone (a-MSH), an important paracrine factor that is required for melanogenic (i.e. tanning) response to solar radiation, protects melanocytes from the carcinogenic effect of UVR by reducing the generation of reactive oxygen species (ROS), increasing the expression and/or activity of antioxidant proteins, and enhancing the repair of oxidative DNA damage. We propose two specific aims: 1) to test the hypothesis that a-MSH exerts its antioxidant effects by modulating the activity of the transcription factor NF-E2-related factor (Nrf-2) and 2) to test the hypothesis that accumulation and transcriptional activity of p53 are necessary for a-MSH reduction of oxidative DNA damage. This proposal will define a new role for a-MSH in UVR photoprotection of hMCs that transcends its classically known effect as an inducer of melanogenesis, and includes reduction of UV-induced oxidative DNA damage, as a possible primary protective mechanism. Public Health Relevance: The incidence of cutaneous malignant melanoma, the deadliest form of skin cancer, continues to rise. The objective of this study is to demonstrate that a-melanocyte stimulating hormone (a-MSH), an important factor for tanning response in the skin, protects melanocytes from the carcinogenic effect of UV by reducing the burden caused by free radicals. In this study, we are proposing to investigate the molecular pathways by which a-MSH counteracts the UV-induced oxidative stress in human melanocytes, and thus prevents their malignant transformation to melanoma.